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A randomised controlled trial of prednisone versus placebo in the management of human immunodeficiency virus (HIV)-infected patients presenting with mild to moderate Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome after commencing Highly Active Antiretroviral Therapy
ISRCTN ISRCTN21322548
DOI 10.1186/ISRCTN21322548
ClinicalTrials.gov identifier
EudraCT number
Public title A randomised controlled trial of prednisone versus placebo in the management of human immunodeficiency virus (HIV)-infected patients presenting with mild to moderate Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome after commencing Highly Active Antiretroviral Therapy
Scientific title
Acronym TB-IRIS-RCT
Serial number at source TB-IRIS-RCT
Study hypothesis We propose a randomised placebo-controlled trial of prednisone as an adjunct in the management of HIV-infected patients with mild to moderate Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome (TB-IRIS). This syndrome manifests as a paradoxical worsening of clinical features of tuberculosis after commencing Highly Active Antiretroviral Therapy (HAART). We hypothesise a reduction in the requirement for hospitalisation and therapeutic procedures among patients receiving prednisone.
Lay summary Not provided at time of registration
Ethics approval Not provided at time of registration
Study design Randomised placebo-controlled trial
Countries of recruitment South Africa
Disease/condition/study domain HIV and Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome
Participants - inclusion criteria A. Age 18 years and over

B. Informed consent (written)

C. Prior to the introduction of HAART the following criteria must be met for the diagnosis of TB-IRIS to be considered:
1. The patient has HIV infection
2. The patient should be antiretroviral-naïve (excluding receipt of antiretroviral treatment within mother to child transmission programmes Ė Nevirapine single-dose with or without Zidovudine in the third trimester)
3. The patient has microbiologic, histologic or very strong clinical evidence of tuberculosis
4. There has been a documented improvement in symptoms, Karnofsky score and/or weight, resolution of fever and clinical and radiological stabilization during the intensive phase of multidrug TB therapy
5. That adherence with anti-TB treatment is >80%
6. That the infecting strain of M. tuberculosis is sensitive to rifampicin, if this result is available

D. Consider TB-IRIS if, within 3 months of the introduction of multi-drug HAART
1. Adherence with HAART is documented and the patient was on anti-tuberculous therapy when HAART commenced
2. There are new or recurrent constitutional symptoms PLUS one or more of:
i. New or expanding lymph nodes (>20 mm or >50% in volume)
ii. New or expanding tuberculous cold abscesses (e.g. paraspinal)
iii. New or expanding pulmonary infiltrates (radiographically confirmed)
iv. New or enlarging serous effusions (pericardial, pleural or ascitic)
Patients presenting with other manifestations of TB-IRIS (e.g. central nervous system [CNS] tuberculoma) will not be included in this study.
Participants - exclusion criteria 1. Previous systemic steroid therapy as part of the management of tuberculosis
2. Pregnancy
3. Uncontrolled Diabetes Mellitus
4. Adrenal failure
5. Severe TB-IRIS (these cases will receive open label corticosteroids) manifested by:
a. Respiratory failure (pO2 <8 kPa)
b. Altered level of consciousness or new focal neurological signs
c. Compression of vital structures (e.g. bronchostenosis)
6. Kaposiís sarcoma
Anticipated start date 01/06/2005
Anticipated end date 31/05/2007
Status of trial Completed
Patient information material
Target number of participants 100
Interventions Randomization to oral prednisone 1.5 mg/kg for 2 weeks followed by 0.75 mg/kg for 2 weeks or identical placebo medication.
Primary outcome measure(s) Combined hospitalisation and procedures endpoint (cumulative duration of hospitalisation in days + outpatient therapeutic procedures counted as one day)
Secondary outcome measure(s) Radiological Endpoints:
A significant improvement in radiological manifestations of IRIS:
1. For Chest X Ray pulmonary infiltrates, a significant reduction in composite infiltrate score (6 zones each measured for degree of infiltrate by Radiologist to give composite score)
2. For large nodes noted on the Chest X Ray, a significant reduction in size
3. For computed tomography (CT) scans, a significant reduction in infiltrate or node size
4. For peripheral & abdominal nodes, a significant reduction in volume as measured by ultrasound
5. For cold abscesses, a significant reduction in volume as measured by ultrasound

Other Secondary Endpoints:
1. 50% reduction in symptom score (Wilson 2004)
2. A significant improvement in the Quality of Life MOS-HIV score
3. Improvement in Karnofsky score of greater than 10
4. Corticosteroid side effects
a. New onset of diabetes
b. New onset of hypertension
c. Psychological side effects
d. Onset of new opportunistic infection/cancer such as Kaposiís sarcoma, Herpes simplex lesions, Herpes zoster lesions
5. 50% reduction in C-Reactive Protein (CRP) value
6. Weight gain
7. Mortality
8. The need to stop HAART, TB therapy or study drug
9. Adherence with HAART and study drug as assessed by pill count and adherence with TB treatment as assessed by TB clinic card assessment
10. Recurrence of IRIS manifestations within the 12 week study period
11. In patients with an Alkaline Phosphatase or gamma glutamyl transpeptidase (GGT) that was elevated more than 2 x upper limit of normal (ULN) at baseline, a reduction of 50% from the baseline value
12. CD4 and Viral load
13. For ascites, reduction in abdominal girth
Sources of funding Medical Research Council, South Africa (no reference number provided)
Trial website
Publications 1. 2012 results in http://www.ncbi.nlm.nih.gov/pubmed/22700860
Contact name Prof  Gary  Maartens
  Address Division of Pharmacology
University of Cape Town Medical School
K45
Old Main Building
Groote Schuur Hospital
  City/town Cape Town
  Zip/Postcode 7925
  Country South Africa
Sponsor University of Cape Town - Research Ethics Committee, Faculty of Health Sciences (South Africa)
  Address Research Ethics Committee
Faculty of Health Sciences
Old Main Building
Groote Schuur Hospital
Observatory
  City/town Cape Town
  Zip/Postcode 7925
  Country South Africa
Date applied 03/06/2005
Last edited 17/08/2012
Date ISRCTN assigned 17/08/2005
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